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Biomedical subjects

A Lucas

Publications and source records attributed to A Lucas.

At least 73 records · Page 4Linked to original sources
PubMed2000

Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin.

BACKGROUND: Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. METHODS AND RESULTS: Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006). CONCLUSIONS: Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.

Animals↗
PubMed2000

Effects of size at birth, gestational age and early growth in preterm infants on glucose and insulin concentrations at 9-12 years.

AIMS/HYPOTHESIS: To test the hypothesis that small size for gestation and poor postnatal growth in preterm infants is associated with higher fasting and post-load plasma glucose and insulin concentrations at 9-12 years of age. METHODS: Prospective follow-up at 9-12 years of 385 preterm children with birth weight less than 1850 g, who had anthropometry recorded at birth, 18 months and 7 years. Fasting plasma glucose, insulin, proinsulin and 32.33 split proinsulin concentrations and glucose and insulin concentrations 30 min after a standard glucose load were measured. RESULTS: Post-load glucose concentrations were negatively related to birth weight, independently of gestation or subsequent growth. Fasting split proinsulin and 30-min insulin concentrations were highest in children who showed the greatest increase in weight centile between birth and current follow-up, regardless of gestation. When weight during childhood was included, birthweight centile was, however, no longer statistically significant: concentrations of fasting, split, proinsulin and 30-min insulin were highest in those children who had shown the greatest increase in weight centile between 18 months of age and current follow-up, with no evidence of a greater effect in those who were smallest at 18 months. CONCLUSION/INTERPRETATION: Our findings suggest that fetal growth influences plasma glucose 30 min after a glucose load in preterm children at 9-12 years. In contrast, childhood weight gain is the most important factor influencing insulin concentrations and this effect is the same regardless of early size.

Blood Glucose↗
PubMed2000

Transplant vasculopathy: viral anti-inflammatory serpin regulation of atherogenesis.

BACKGROUND: Surgical and ischemic injury to the artery wall initiates vascular wound-healing responses that stimulate atherosclerotic plaque growth. The plasminogen activators have cellular chemotactic, adhesion, and proteolytic activity. Serp-1 is a secreted myxoma virus glycoprotein serpin that binds and inhibits plasminogen activators. We have examined the effects of Serp-1 on plaque growth and inflammatory cell invasion in animal models after balloon injury and after aortic allograft transplant. METHODS: We used histologic analysis to assess 4 animal models of angioplasty-mediated injury and 2 models of aortic allograft transplant for intimal hyperplasia and cellular invasion. We assessed plasminogen activator (uPA and tPA) and inhibitor (PAI-1) expression in rat iliofemoral arteries after balloon injury using Western blot, enzyme activity, and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Plaque growth after balloon injury decreased after Serp-1 treatment in all balloon-injury models tested. Transplant vasculopathy also significantly decreased in 2 rat models of aortic allograft transplant. Infusion of a Serp-1 active site mutant, that lacked plasminogen activator inhibiting activity, did not inhibit plaque growth. Quantitative RT-PCR detected increased transcription of PAI-1 mRNA. Increased PAI-1 protein and enzyme-inhibitory activity was also detected in Serp-1-treated arteries by activity assay and Western blot. CONCLUSIONS: Thrombolytic serpins are central regulatory agents in vascular wound-healing responses. Investigation of the inhibitory mechanisms of viral serpins may provide new insights into atherogenesis.

Angioplasty, Balloon↗
PubMed2000

Metabolism and distribution of the virus-encoded serine proteinase inhibitor SERP-1 in healthy rabbits.

SERP-1 is a secreted myxoma virus-encoded 55-kd protein of the serine proteinase inhibitor ("serpin") family that strongly inhibits the mitosis of medial arterial smooth muscle cells, thus preventing stenosis in injured rabbit and rat arteries. We have measured the fractional catabolic rate (FCR) and compartmental distribution of 1251-SERP-1 after injection of various doses into the circulation of healthy rabbits. The FCR within the intravascular space decreased from 2.99 d(-1) to 2.39 d(-1) and the whole-body FCR decreased from 0.66 d(-1) to 0.51 d(-1) as the dose was increased 35-fold from 0.11 microg/kg to 3.8 microg/kg. The fractional distribution of SERP-1 between the intravascular (0.21), noncirculating vascular wall (0.09), and extravascular compartments (0.70) at equilibrium did not change significantly over this dose range. SERP-1 did not appear to selectively accumulate in any organ in any of 11 rabbits studied over a 6-day interval. In comparison to other rabbit plasma serpins, the behavior of SERP-1 in vivo most closely resembled that of heparin cofactor II.

Animals↗
PubMed2000

Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease?

OBJECTIVES: Preterm infants are known to remain small during childhood. We previously found that evidence of neonatal metabolic bone disease was associated with reduced length at 18 months. We aimed to further investigate factors predicting childhood height and to test the hypothesis that evidence of early metabolic bone disease is associated with reduced later height. STUDY DESIGN: A cohort of preterm infants was measured prospectively at 18 months (n = 765), 7. 5 to 8 years (n = 772), and 9 to 12 years of age (n = 503). RESULTS: Preterm infants remained short for their age and sex at all follow-ups. Later height was most strongly predicted by parental height and, at 9 to 12 years, by pubertal status. Neonatal factors associated with later height were birth weight SD score, maternal hypertension/toxemia, and a high peak plasma alkaline phosphatase during the neonatal period. After adjustment for these factors plus interim heights, height at 9 to 12 years was greatest in those who were tallest at 7.5 to 8 years, those who had shown the greatest increase in height percentile between 18 months and 7.5 to 8 years and, as expected, those who were pubertal, whereas children with a peak neonatal plasma alkaline phosphatase >1200 IU were significantly shorter. CONCLUSIONS: Childhood height in preterm infants is strongly influenced by genetic factors. However, biochemical evidence of metabolic bone disease during the neonatal period may have a long-term stunting effect persisting up to 12 years later, providing support for current practices that aim to prevent this condition.

Body Height↗
PubMed2000

Effects of growth during infancy and childhood on bone mineralization and turnover in preterm children aged 8-12 years.

To investigate the effect of growth on later bone mass and turnover, bone mineral content (BMC) and density (BMD: dual X-ray absorptiometry (QDR 1000W) and single photon absorptiometry (Lunar SP2)) and bone turnover (plasma osteocalcin, urine deoxypyridinoline) were measured at 8-12 y in 244 preterm children who had weight and height measured at 18 mo and 7.5-8 y corrected age. Weight and length at birth, 18 mo, 7.5-8 y and current follow-up showed increasingly strong, positive correlations with bone area, BMC and BMD. After adjusting for current size, there were significant negative associations between earlier size measurements and later whole body and lumbar spine bone mass which were stronger for length than for weight, and a negative relationship between birthweight for gestation and later radial bone mass; but no relationship with bone turnover. Current calcium intake and activity level had no independent effect on bone mass. Bone mass at 8-12 y is related to current bone and body size, which tracks throughout childhood. However, amongst children of the same current size, those who have shown the greatest increase in size, particularly in height, have the highest bone mass. These findings raise the hypothesis that improving linear growth in vulnerable children may be important in maximizing bone mass.

Absorptiometry, Photon↗
PubMed2000

Birthweight and social deprivation: influences on serum lipids and fibrinogen.

UNLABELLED: Epidemiological studies have shown that adults with low birthweight have a higher risk of cardiovascular disease and some others have shown that they have a less favourable serum lipid and lipoprotein profile. If cholesterol metabolism were programmed in utero, we would expect to see an influence of birthweight on blood lipids in children. In 422 children aged 11-15 y in Middlesborough, Cleveland, UK, we investigated the association between birthweight and serum lipids and plasma fibrinogen. We also investigated the influence of childhood social deprivation, measured using the Townsend deprivation index, on these measures. CONCLUSIONS: We found a significant inverse association between birthweight and serum triglyceride level, but not with other serum lipid levels. From a regression model we estimate that triglyceride rose by 1.1 mmol l(-1) kg(-1) fall in birthweight after adjustment for sex, current age and weight. Findings were similar in boys and girls separately. This could contribute to the observed inverse association between birthweight and cardiovascular mortality. Social deprivation was associated with higher fibrinogen, but not lipid levels. Our data highlight the importance of considering influences throughout the life course on adult disease.

Adolescent↗
PubMed2000

Postpartum thyroiditis: epidemiology and clinical evolution in a nonselected population.

Postpartum thyroiditis (PPT) presents in approximately 5% of women. Its incidence, clinical characteristics, and evolution were studied in a nonselected population of Mediterranean women. Six hundred five healthy women, recruited between the 36th week of pregnancy and the 4th postpartum day, underwent initial clinical and biological evaluation and postpartum at 1 (n = 605), 3 (n = 552), 6 (n = 574), 9 (n = 431), and 12 (n = 444) months. PPT was diagnosed in women with transient hyperthyroidism between 1 and 3 months postpartum and/or hypothyroidism between 3 and 6 months postpartum. Permanent hypothyroidism was considered if it was overt and persisted one year after diagnosis. The incidence rate of PPT was 7.8%. Eighty-two percent of PPT patients had hormone abnormalities at the 6th month postpartum, 8.8% showed depression and 51% goiter. PPT was manifest as hyperthyroidism plus hypothyroidism in 35.5% of patients, because only transient hyperthyroidism in 22.2% and as hypothyroidism alone in 42.3%. Five patients with hypothyroidism during PPT (0.82% of the initial population, 11.1% of PPT patients, and 15.6% of hypothyroidism PPT patients) presented permanent hypothyroidism after a follow-up of 39.8 (4.2) months. PPT was found in 7.8% of general Mediterranean population. We recommend evaluation at the 6th postpartum month to diagnose the majority of PPT women and indefinite follow-up of hypothyroid PPT patients to detect permanent hypothyroidism.

Adolescent↗
PubMed2000

Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children.

BACKGROUND: Preterm children are at high risk of poor growth performance. In 2 randomized trials, preterm infants fed preterm formula grew better in the neonatal period than those fed banked donor breast milk or standard term formula. OBJECTIVE: Our objective was to test the hypothesis that for preterm infants, the neonatal period is a critical one for programming growth performance and that early diet influences long-term growth. DESIGN: A total of 926 preterm infants were recruited into 2 parallel, randomized trials of neonatal diet. In trial 1, infants were fed either banked donor breast milk or preterm formula whereas in trial 2, infants were fed either standard term formula or preterm formula. Within each trial, the allocated milk was the sole diet for some infants (study A), whereas for others it was a supplement to maternal breast milk, given when not enough expressed breast milk was available (study B). We followed up 781 of 833 survivors (94%) to age 7.5-8 y. Trained assessors obtained anthropometric measurements according to a standard protocol. RESULTS: Despite significantly better neonatal growth performance in infants fed preterm formula (compared with either banked donor breast milk or standard formula), early diet had no influence on weight, height, head circumference, or skinfold thicknesses at 9 or 18 mo postterm or at age 7.5-8 y. CONCLUSIONS: These findings suggest that the preterm period is not a critical window for nutritional programming of growth, which contrasts with evidence from these trials showing that early diet influences later neurodevelopment.

Body Height↗
PubMed2000

Mycobacterium genavense infection in two aged ferrets with conjunctival lesions.

Mycobacterium genavense infection was diagnosed in two adult ferrets. Disseminated mycobacteriosis was diagnosed in a castrated 5-year-old sable ferret with generalised peripheral lymph node enlargement and a proliferative lesion of the conjunctiva of the nictitating membrane. The diagnosis was based on characteristic cytology and sequence analysis of the 16S rRNA gene amplified using the polymerase chain reaction from fresh biopsy material. Therapy with rifampicin, clofazimine and clarithromycin probably cured the infection. An entire 4-year-old female ferret with conjunctival swelling, serous ocular discharge and swelling of the subcutaneous tissues of the nasal bridge was diagnosed as having M genavense infection on the basis of typical cytology, histopathology and sequence analysis of 16S rRNA amplicons from formalin-fixed paraffin-embedded tissue. This patient was treated successfully using rifampicin. Both ferrets subsequently died as a result of other disease conditions, 10 and 4 months following initiation of therapy, respectively. This is the first report documenting M genavense as a cause of disseminated mycobacterial disease in ferrets. Conjunctival involvement may be a feature of disseminated mycobacteriosis in the ferret. The possibility that these infections were the consequence of a ferret retrovirus infection should be considered further.

Animals↗
PubMed2000

The viral anti-inflammatory chemokine-binding protein M-T7 reduces intimal hyperplasia after vascular injury.

Chemokines and IFN-gamma function as central regulators of inflammatory responses to vascular injury. Both classes of cytokines are upregulated during restenosis, a response to vascular injury that leads to recurrent atherosclerotic plaque growth, but the relative impact of each class of cytokines remains undetermined. M-T7 is a secreted myxoma viral immunomodulatory glycoprotein that functions both as a species-specific inhibitor of rabbit IFN-gamma and as a chemokine-binding protein, interacting with a wide range of C, C-C, and C-X-C chemokines in a species-nonspecific fashion. We wished to (a) assess the efficacy of purified M-T7 protein in inhibiting intimal hyperplasia after angioplasty injury and (b) exploit unique species-specific functions of M-T7 in order to judge the relative importance of each cytokine class on plaque growth. Anesthetized New Zealand white rabbits and Sprague-Dawley rats received either M-T7 or control at the time of arterial angioplasty injury. Histological analysis at 28 days demonstrated significant reductions in intimal hyperplasia with M-T7 treatment in both models, with an associated early inhibition of inflammatory cell invasion. Purified M-T7 protein inhibits intimal hyperplasia after angioplasty injury in a species-nonspecific fashion, thus implicating the chemokine-binding activity as more critical for prevention of plaque growth after vascular injury.

Animals↗
PubMed2000

Mode of delivery and childhood blood pressure.

A number of studies have shown that children born by cesarean section have lower blood pressure during the neonatal period. The aim of this study was to investigate whether mode of delivery influenced childhood blood pressure: at age 7.5 to 8 y in a cohort of 756 children born preterm, at 7 to 9 y in a pilot study of 166 children born at term in the United Kingdom, and in a cohort of 650 Tasmanian children born at term. In the preterm cohort, systolic blood pressure was significantly lower in children born by cesarean section rather than delivered vaginally (99.3+/-10.0 versus 101.4+/-9.4 mm Hg; 95% confidence interval, -0.69 to -3.46; p = 0.003), with a significant trend to having a higher pressure in those born by breech versus forceps versus spontaneous vaginal delivery versus cesarean section. These findings were not replicated in the term cohorts. This raises the hypothesis that there is a sensitive period for programming later blood pressure by factors associated with mode of delivery and that this period does not extend to full-term.

Blood Pressure↗
PubMed2000

Hippocampal volume and everyday memory in children of very low birth weight.

Children born preterm and of very low birth weight have an increased incidence of learning difficulties, but little is known about the specific nature of their cognitive deficits and the underlying neuropathology. We hypothesized that their vulnerability to hypoxic, metabolic, and nutritional insults would lead to reduced hippocampal volumes and to deficits in memory because of the role of the hippocampus in this domain of cognition. Neuropsychological and magnetic resonance imaging methods were used to investigate this hypothesis in adolescents born preterm (< or = 30 wk gestation, n = 11) or full-term (n = 8). The preterm group had significantly smaller hippocampal volumes bilaterally, despite equivalent head size, and showed specific deficits in certain aspects of everyday memory, both on objective testing and as indicated by parental questionnaires. The preterm group also had a specific deficit in numeracy. The reduced hippocampal volumes and deficits in everyday memory have previously been unrecognized, but their prevalence in a group of neurologically normal children is striking.

Adolescent↗
PubMed2000

The moon has four phases and that's what worries me.

The values held by health care administrators and inherent in the operation of the institution are of primary importance to the ministry of pastoral care. This narrative/story provides a case history in which the author recounts how these values change as administrators change. The results suggest that these values constitute one of the hidden variables that influenced the questionnaire results reported earlier in this work.

Attitude of Health Personnel↗
PubMed2000

Diagnostic efficiency of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH measurements in the diagnosis of adult GH deficiency: importance of an appropriate reference population.

OBJECTIVE: To analyse the diagnostic role of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH (uGH) excretion in adult GH deficiency (GHD). DESIGN: Twenty-seven adults (age range: 18-71 years) with severe GHD, defined by a peak GH response to an insulin tolerance test below 3microg/l in patients with at least one additional pituitary hypofunction. Reference values were established from a selected age- and body mass index-matched population (154 healthy adults grouped in four age groups). METHODS: IGF-I and IGFBP-3 were measured by RIA (Nichols) and results expressed as standard deviation (s.d.) scores from our reference population and assay normative data (s.d. score Nichols). uGH was measured by IRMA. RESULTS: Within the control group, IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio standardisation regarding our control population and IGF-I with respect to the assay normative data resulted in disappearance of age-related differences. However, IGFBP-3 s.d. score Nichols resulted in mean values between +1.4 and +2.5 s.d. score. Greatest diagnostic efficiency was for IGF-I standardised with respect to our controls (97.2%), followed by s.d. score IGFBP-3 (92.9%). s.d. score IGF/IGFBP-3 ratio and uGH showed poor diagnostic efficiency. Any combination of at least two abnormal parameters raised specificity to 100%. IGF-I standardised with respect to assay reference (s.d. score Nichols) showed similar diagnostic value (95.0%) whereas IGFBP-3 showed low sensitivity (33. 3%). Within the GHD patients, those with three or more additional deficiencies had lower s.d. score IGF-I than those with only two or one. CONCLUSION: We underline the importance of an appropriate reference population for correct interpretation of GH secretion markers. Considering our results, specificity obtained with two simultaneous abnormal parameters when referred to an adequate reference population may add valuable information to alternative GH stimulation tests to confirm adult GHD.

Adult↗